Endocrine Unit: Bastepe Laboratory

GNAS encodes the α-subunit of the stimulatory G protein (Gsα), a signaling protein that mediates the actions of numerous hormones, neurotransmitters and autocrine/paracrine factors. Mutations of GNAS are associated with several human diseases, including McCune-Albright syndrome, Albright’s hereditary osteodystrophy, progressive osseous heteroplasia and pseudohypoparathyroidism. A variant of Gsα is the so-called extra-large α-subunit (XLαs), which uses a different first exon and an upstream promoter that is active exclusively on the paternal allele. Unlike Gsα, the cellular role of XLαs is unclear. Nonetheless, data from XLαs "knockout" mice and children with large deletions of the paternal GNAS allele indicate that XLαs is essential at least for postnatal adaptation to feeding and to glucose and energy metabolism. In addition, nearly all mutations of GNAS affect both Gsα and XLαs. Yet, the significance of XLαs deficiency or overactivity in the pathogenesis of these diseases is unknown. Our lab aims to elucidate the cellular roles of XLαs and understand how alterations in XLαs activity, together with alterations in Gsα activity, contribute to GNAS-related disease pathogenesis. Our research primarily focuses on the mechanisms that govern the defects in bone and kidney, and we investigate both diseases caused by activating GNAS mutations (such as McCune-Albright syndrome and fibrous dysplasia of bone) and diseases caused by inactivating GNAS mutations (such as pseudohypoparathyroidism and progressive osseous heteroplasia).

Gsα is expressed biallelically in many tissues, but the paternal Gsα promoter is repressed in certain tissues such as renal proximal tubules, pituitary, gonads and thyroid. Due to this genomic imprinting event, heterozygous inactivating mutations of GNAS lead to hormone resistance (i.e. pseudohypoparathyroidism) when located on the maternal allele. The same mutations do not impair hormone actions when located on the paternal allele. Likewise, GNAS mutations that cause constitutive Gsα activity appear to cause growth hormone-secreting pituitary adenomas only when they occur on the maternal allele. However, the molecular mechanisms underling the tissue-specific paternal imprinting of Gsα are poorly understood. We currently investigate the developmental regulation of these mechanisms in various tissues, including kidney and brown fat, and aim to advance the knowledge of the diseases caused by GNAS mutations.